Premed · Premed · Organic Chemistry 2
Lecture 16: Carbohydrates: Monosaccharides
Organic Chemistry II
Learning Objectives
By the end of this lecture, students will be able to:
- Define carbohydrates and classify them as monosaccharides, disaccharides, and polysaccharides
- Draw and name monosaccharides using Fischer projections
- Classify sugars as aldoses/ketoses and by carbon number (triose, tetrose, pentose, hexose)
- Assign D and L configurations to monosaccharides
- Identify epimers, anomers, and enantiomers
- Draw cyclic (Haworth and chair) structures and explain mutarotation
- Describe key reactions of monosaccharides
Lecture Content
I. Introduction to Carbohydrates
Carbohydrates have the approximate general formula Cn(H2O)n, which gives rise to the name "carbo-hydrate," though this formula is only an approximation. Structurally, carbohydrates are polyhydroxy aldehydes, polyhydroxy ketones, or compounds that yield these upon hydrolysis. They are classified by size: monosaccharides are the simplest units and cannot be hydrolyzed further; disaccharides consist of two monosaccharides linked by a glycosidic bond; oligosaccharides contain three to ten units; and polysaccharides such as starch, cellulose, and glycogen contain many hundreds or thousands of units.
Carbohydrates are further classified by functional group: aldoses contain an aldehyde group, while ketoses contain a ketone (usually at C2). They are also described by their carbon number as trioses (3C), tetroses (4C), pentoses (5C), or hexoses (6C). These terms combine to give descriptions such as aldohexose or ketopentose. The biological importance of carbohydrates is immense: they serve as primary energy sources, structural components (cellulose, chitin), cell-recognition elements (glycoproteins), and essential parts of the nucleic acid backbone (ribose, deoxyribose).
II. Fischer Projections and Stereochemistry
Fischer projections represent monosaccharides with the carbon chain drawn vertically, C1 (the most oxidized carbon) at the top, vertical bonds going back into the page, and horizontal bonds coming forward out of the page. Each stereocenter is explicitly shown.
The stereochemical complexity of sugars is considerable. An aldohexose has four stereocenters, yielding 2^4 = 16 possible stereoisomers, which constitute eight D/L pairs. The eight D-aldohexoses are allose, altrose, glucose, mannose, gulose, idose, galactose, and talose. The D or L designation is assigned based on the configuration at the highest-numbered stereocenter (the one farthest from the carbonyl). In a D-sugar, the hydroxyl on this carbon points to the right in the Fischer projection; in an L-sugar, it points to the left. Critically, D and L designations indicate configuration, not optical rotation: D-glucose happens to be dextrorotatory, but D does not inherently mean (+).
Most naturally occurring sugars are D-sugars. Important stereochemical relationships exist among them. Enantiomers are mirror images with all stereocenters inverted (D-glucose and L-glucose). Diastereomers differ at one or more but not all stereocenters. Epimers are a special case of diastereomers that differ at exactly one stereocenter: D-glucose and D-mannose are C2 epimers, while D-glucose and D-galactose are C4 epimers.
<image>The family tree of D-aldoses from D-glyceraldehyde (a triose) branching down through D-tetroses (erythrose, threose), D-pentoses (ribose, arabinose, xylose, lyxose), and D-hexoses (allose, altrose, glucose, mannose, gulose, idose, galactose, talose). Each sugar is shown as a Fischer projection with all stereocenters drawn. D-glucose, D-mannose, and D-galactose are highlighted, and the C2 epimer relationship between glucose and mannose, and the C4 epimer relationship between glucose and galactose, are indicated with connecting lines.</image>
III. Cyclic Structures of Monosaccharides
Monosaccharides with five or more carbons exist predominantly as cyclic hemiacetals rather than in the open-chain form. The cyclic structure forms through an intramolecular reaction between the carbonyl group and a hydroxyl group within the same molecule. Aldohexoses typically form pyranose rings (six-membered rings resembling pyran) when the hydroxyl at C5 attacks the C1 aldehyde. Aldopentoses and ketohexoses can form furanose rings (five-membered rings resembling furan).
Ring closure creates a new stereocenter at the former carbonyl carbon, called the anomeric carbon. In the alpha anomer, the hydroxyl on the anomeric carbon is axial (or, in a Haworth projection of a D-sugar, pointing down). In the beta anomer, this hydroxyl is equatorial (pointing up in the Haworth projection). Haworth projections represent the ring as a flat structure, with groups on the right side of the Fischer projection pointing down and groups on the left pointing up.
Chair conformations provide the most accurate depiction of pyranose ring geometry. Beta-D-glucopyranose is particularly noteworthy because all of its bulky substituents (-OH groups and the -CH2OH group) occupy equatorial positions, making it the most stable hexose. This thermodynamic stability helps explain the extraordinary abundance of glucose in the biological world.
IV. Mutarotation
Mutarotation is the gradual change in optical rotation observed when a pure anomer of a sugar is dissolved in water. The cyclic hemiacetal opens to the open-chain aldehyde form, which can then re-close to give either the alpha or beta anomer. Over time, an equilibrium mixture is established.
For D-glucose, pure alpha-D-glucopyranose has a specific rotation of +112 degrees, pure beta-D-glucopyranose has +18.7 degrees, and the equilibrium mixture settles at +52.7 degrees. At equilibrium, approximately 36% of the molecules are in the alpha form and 64% in the beta form, with less than 0.01% present as the open-chain aldehyde at any given moment. The beta anomer predominates because its all-equatorial arrangement of substituents makes it thermodynamically more stable. Both acid and base catalyze mutarotation.
<image>Panel A: Mechanism of mutarotation showing the interconversion of alpha-D-glucopyranose (chair conformation, anomeric OH axial) through the open-chain aldehyde form to beta-D-glucopyranose (chair conformation, anomeric OH equatorial). Curved arrows show the ring opening and ring closing steps. Panel B: A graph of optical rotation vs. time showing the change from the initial value of either pure anomer to the equilibrium value of +52.7 degrees. Two curves are shown: one starting at +112 (alpha) decreasing, and one starting at +18.7 (beta) increasing, both converging at +52.7.</image>
V. Reactions of Monosaccharides
Oxidation reactions are central to sugar chemistry. The Tollens' test (Ag+/NH3) and the Benedict's/Fehling's test (Cu2+) identify reducing sugars -- any sugar with a free anomeric hydroxyl that can equilibrate with the open-chain aldehyde. Bromine water selectively oxidizes the aldehyde end to give an aldonic acid (glucose becomes gluconic acid), while nitric acid oxidizes both ends to give an aldaric acid (a dicarboxylic acid). Periodic acid (HIO4) cleaves vicinal diols and was historically important for sugar structure determination.
Reduction of the carbonyl with NaBH4 yields a sugar alcohol (alditol). Glucose gives glucitol (sorbitol), a common sugar substitute, while mannose gives mannitol.
Osazone formation with three equivalents of phenylhydrazine modifies C1 and C2, producing a crystalline derivative. Notably, C2 epimers (such as glucose and mannose) give the same osazone because the C2 stereocenter is destroyed during the reaction. This property was historically used to identify sugars and establish their stereochemical relationships.
Treatment with an alcohol under acid catalysis converts the hemiacetal at the anomeric position to a full acetal, called a glycoside. The new bond is a glycosidic bond. Glycosides are not reducing sugars because the anomeric carbon is locked as an acetal and can no longer open to the free aldehyde under neutral or basic conditions. Glycosides are cleaved by aqueous acid or by specific glycosidase enzymes.
Methylation of all free hydroxyl groups (with CH3I/Ag2O) and acetylation (with Ac2O/pyridine) are used for structural analysis and as protection strategies in synthesis.
<image>Reaction summary map centered on D-glucose (in its open-chain Fischer projection form). Arrows radiate to six products: (1) gluconic acid (Br2/H2O oxidation of C1), (2) glucaric acid (HNO3 oxidation of C1 and C6), (3) glucitol/sorbitol (NaBH4 reduction), (4) osazone (PhNHNH2), (5) methyl glucoside (MeOH/H+), and (6) glucopyranose (cyclization). Each product structure is drawn and labeled with the reagents used.</image>
